Abstract
The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other “eat me” signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re-evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully elucidated.Graphical abstract
Highlights
Cell death is central to physiological homeostasis; the balance between cellular differentiation, proliferation, and death underpins all aspects of biology, including embryogenesis, organ function, immune responsivity, Apoptosis Defined in 1972, apoptosis was the first form of regulated cell death (RCD) to be discovered [3]
Concluding remarks Exposure of PS by non-apoptotic cells has long been disregarded, leading to the role of PS exposure during apoptosis being overstated with respect to how inflammation is mitigated during apoptosis
We have outlined the evidence for PS exposure in nonapoptotic cells and extracellular vesicles (EVs), discussed a potential mechanism, and looked at the effect of PS-exposure on the reversibility of cell death, the phagocytosis of dead cells, and subsequent inflammation
Summary
Cell death is central to physiological homeostasis; the balance between cellular differentiation, proliferation, and death underpins all aspects of biology, including embryogenesis, organ function, immune responsivity, Apoptosis Defined in 1972, apoptosis was the first form of regulated cell death (RCD) to be discovered [3]. Another main feature is the exposure of phosphatidylserine (PS) on the outer plasma membrane, which, among other “eat me” signals, results in the phagocytosis and clearance of apoptotic cells and bodies without the release of pro-inflammatory molecules [21].
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